As an essential nutrient, manganese is required for the function of numerous enzymes. Through these enzymes, manganese plays important roles in human health. Manganese deficiency leads to impaired growth, osteoporosis, dyslipidemia, asthma, and cognitive defects. Manganese overload, on the other hand, produces a spectrum of neurological and behavioral defects, clinically known as manganism. Therefore, manganese homeostasis needs to be tightly controlled to meet the dual challenge of avoiding deficiency and overload. Manganese transporters play critical roles in this control. ZIP14 (Zrt- and Irt-like protein, member 14, or SLC39A14) is a newly identified manganese importer. It is highly expressed in the small intestine and liver, that are the two major organs involved in the control of manganese metabolism. Patients with loss-of-function mutations in ZIP14 developed severe childhood-onset manganese overload, indicating an indispensable role for ZIP14 in maintaining body manganese homeostasis. However, the precise mechanism of this disease has not been determined. The goal of this proposed research is to determine the function of ZIP14 in regulating manganese homeostasis and to elucidate how ZIP14 mutations lead to manganese toxicity. This application focuses on ZIP14?s function at two levels: its role in regulating cellular manganese transport and its function in balancing whole-body manganese homeostasis. We will use a combination of cell assays and genetically modified mouse models to identify new factors that determine ZIP14?s function and to investigate the physiological significance of new findings in disease biology. Our proposed research will provide a more comprehensive understanding of how manganese homeostasis is controlled and how manganese overload is induced in individuals lacking functional ZIP14. This project will have great potential for identifying novel therapeutic targets and developing effective prevention strategies that would minimize adverse health impacts occurred in patients